Cyclopropyl aryl amide derivatives and uses thereof

ABSTRACT

Compounds of the formula: 
     
       
         
         
             
             
         
       
     
     wherein Ar 1 , Ar 2 , R 1  and R 2  are as defined herein. Also provided are pharmaceutical compositions, methods of using, and methods of preparing the subject compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalPatent Application Ser. No. 60/997,581, filed Oct. 4, 2007, thedisclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to nicotinic acetylcholine receptor ligands(nAChR), and particularly to positive allosteric modulators for the a7nAChR subtype, and methods of making and using such compounds.

BACKGROUND OF THE INVENTION

Nicotinic acetylcholine receptors (nAChR) are members of theligand-gated ion channel family. When activated, the conductance of ionsacross the nicotinic ion channels increases. Nicotinic alpha 7 receptor(alpha 7 nAChR) forms a homopentameric channel in vitro that is highlypermeable to calcium cations. Each alpha 7 nAChR has four transmembranedomains, known as M1, M2, M3, and M4. The M2 domain has been suggestedto form the wall lining the channel. Sequence alignment shows that thealpha 7 nAChR is highly conserved during evolution. The M2 domain thatlines the channel is identical in protein sequence from chick to human.Alpha 7 nAChR is described by, Revah et al. (1991), Nature, 353,846-849; Galzi et al. (1992), Nature 359, 500-505; Fucile et al. (2000),PNAS 97(7), 3643-3648; Briggs et al. (1999), Eur. J. Pharmacol. 366(2-3), 301-308; and Gopalakrishnan et al. (1995), Eur. J. Pharmacol.290(3), 237-246.

The alpha 7 nAChR channel is expressed in various brain regions and isbelieved to be involved in many important biological processes in thecentral nervous system (CNS), including learning, memory and attention(Levin et al., Psychopharmacology (1998), 138, 217-230). Alpha 7 nAChRare localized on both presynaptic and postsynaptic terminals and havebeen suggested to be involved in modulating synaptic transmission.Agonists of alpha 7 nAChR have been shown to improve attention andcognition in Alzheimer's and attention deficit disorder conditions(Wilens et al., Am. J. Psychiatry (1999), 156(12), 1931-1937).

The analgesic effects of nicotine have long been known. Agonists of thealpha 7 nAChR receptor have been shown to modulate production ofpro-inflammatory cytokines, including interleukins (ILs), tumor necrosisfactor (TNF) alpha, and high-mobility group box (HMGB-1), and to inhibitinflammatory signalling in the CNS (de Jonge et al., Br. J. Pharmacol.(2007), 1-15). The alpha 7 nAChR receptor has a role in modulating CNSpain transmission, and alpha 7 nAChR agonists have shown anantinociceptive effect in an acute pain model (Damaj et al.,Neuropharmacol. (2000) 39, 2785-2791.

Since acetylcholine (ACh) is an endogenous agonist of alpha 7 nAChR,agonists that act at the same site as ACh can stimulate and possiblyblock receptor activity through desensitization and competitive blockadeprocesses (Forman et al., Biophysical J. (1988), 54(1), 149-158) andlead to prolonged receptor inactivation (Buisson et al., J. Neurosci.(2001), 21(6), 1819-1829). Desensitization limits the duration that theion channel remains activated during agonist application. Thus theenhancement of Alpha 7 nAChR activity provided by such agonists willalso increase competition with ACh, and therefore limit the usefulnessof agonists as drugs.

Positive allosteric modulators of the nicotinic alpha 7 receptor channelenhance the activity of ACh and other nicotinic alpha 7 receptoragonists. Positive allosteric modulators activate alpha 7 nAChR whensufficient ACh is present in the central nervous system. Positiveallosteric modulators of alpha 7 nAChRs thus are useful for treatment ofCNS, pain and inflammatory diseases or conditions, to regulate CNSfunctions such as cognition, learning, mood, emotion and attention, andcontrol production of pro-inflammatory cytokines associated with painand inflammatory conditions. There is accordingly a need for newpositive allosteric modulators of the the nicotinic alpha 7 receptorchannel.

SUMMARY OF THE INVENTION

One aspect of the invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Ar¹ and Ar2 each independently is:        -   optionally substituted aryl; or        -   optionally substituted heteroaryl; and    -   R¹ and R² each independently is:        -   hydrogen;        -   fluoro;        -   C₁₋₆alkyl; or        -   halo-C₁₋₆alkyl.

The invention also provides pharmaceutical compositions and methods ofusing the aforementioned compounds.

In another aspect of the invention there is provided a method forpreparing a compound of formula r

wherein Ar¹, Ar², R¹ and R² are as defined herein, the methodcomprising:

reacting a cinnamate compound of formula s

with a Wittig reagent of formula t

to form a cyclopropylester compound of formula u

hydrolyzing the cyclopropyl ester compound of formula u to afford acyclopropyl acid compound of formula p

treating the cyclopropyl acid compound of formula p with chloroformateester, followed by sodium azide and acidification, to afford acyclopropyl amine compound of formula

reacting the cyclopropyl amine compound of formula q with an acylreagent of formula i

wherein X is hydroxy, halo or alkoxy, to form the compound of formula r.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Agonist” refers to a compound that enhances the activity of anothercompound or receptor site.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms, i.e. C₁-C₆alkyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.“Branched alkyl” means isopropyl, isobutyl, tert-butyl,

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkoxy” means a moiety of the formula —OR, wherein R is an alkyl moietyas defined herein. Examples of alkoxy moieties include, but are notlimited to, methoxy, ethoxy, isopropoxy, tert-butoxy and the like.

“Alkoxyalkyl” means a moiety of the formula —R′—R″, where R′ is alkyleneand R″ is alkoxy as defined herein. Exemplary alkoxyalkyl groupsinclude, by way of example, 2-methoxypropyl, 3-methoxypropyl,1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and1-(2-methoxyethyl)-3-methoxypropyl.

“Alkylcarbonyl” means a moiety of the formula —C(O)—R, where R′ is alkylas defined herein.

“Alkylsulfonyl” means a moiety of the formula —SO₂—R′ where R′ is alkylas defined herein.

“Amino” means a moiety of the formula —NRR′ where R and R′ eachindependently is hydrogen or alkyl as defined herein.

“Aminosulfonyl” means a moiety of the formula —SO₂—R′ where R′ is aminoas defined herein.

“Alkylsulfonylalkyl” means a moiety of the formula —R^(b)—SO₂—R^(a),where R^(a) is alkyl and R^(b) is alkylene as defined herein. Exemplaryalkylsulfonylalkyl groups include, by way of example,3-methanesulfonylpropyl, 2-methanesulfonylethyl, 2-methanesulfonylpropy,and the like.

“Alkylsulfonyloxy” means a moiety of the formula R^(a)—SO₂—O—, whereR^(a) is alkyl as defined herein.

“Antagonist” refers to a compound that diminishes or prevents the actionof another compound or receptor site.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, phenyl, naphthyl, phenanthryl,fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl,methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl,diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl,benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl,benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl,methylenedioxyphenyl, ethylenedioxyphenyl, and the like, includingpartially hydrogenated derivatives thereof, each of which may beoptionally substituted. A preferred aryl is optionally substitutedphenyl.

“Aryloxy” means a moiety of the formula —OR, wherein R is an aryl moietyas defined herein.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical-R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is an arylgroup as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Aralkoxy” means a moiety of the formula —OR, wherein R is an aralkylmoiety as defined herein.

“Cyanoalkyl” means a moiety of the formula —R′—R″, where R′ is alkyleneas defined herein and R″ is cyano or nitrile.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consistingof mono- or bicyclic rings. Cycloalkyl can optionally be substitutedwith one or more substituents, wherein each substituent is independentlyhydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, ordialkylamino, unless otherwise specifically indicated. Examples ofcycloalkyl moieties include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like,including partially unsaturated derivatives thereof.

“Cycloalkyloxy” and “cycloalkoxy”, which may be used interchangeably,mean a group of the formula —OR wherein R is cycloalkyl as definedherein. Exemplary cycloalkyloxy include cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and the like.

“Cycloalkylalkyl” means a moiety of the formula —R′—R″, where R′ isalkylene and R″ is cycloalkyl as defined herein.

“Cycloalkylalkyloxy” and “cycloalkylalkoxy”, which may be usedinterchangeably, mean a group of the formula —OR wherein R iscycloalkylalkyl as defined herein. Exemplary cycloalkyloxy includecyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy,cyclohexylmethoxy and the like.

“Heteroalkyl” means an alkyl radical as defined herein, including abranched C₄-C₇-alkyl, wherein one, two or three hydrogen atoms have beenreplaced with a substituent independently selected from the groupconsisting of —OR^(a), —NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is aninteger from 0 to 2), with the understanding that the point ofattachment of the heteroalkyl radical is through a carbon atom, whereinR^(a) is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; R^(b)and R^(c) are independently of each other hydrogen, acyl, alkyl,cycloalkyl, or cycloalkylalkyl; and when n is 0, R^(d) is hydrogen,alkyl, cycloalkyl, or cycloalkylalkyl, and when n is 1 or 2, R^(d) isalkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino, ordialkylamino. Representative examples include, but are not limited to,2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl,2,3-dihydroxybutyl, 2-hydroxy-1-methylpropyl, 2-aminoethyl,3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl,aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

“Heteroaryl” means a monocyclic, bicyclic or tricyclic radical of 5 to12 ring atoms having at least one aromatic ring containing one, two, orthree ring heteroatoms selected from N, O, or S, the remaining ringatoms being C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl,pyrazinyl, thienyl, thiophenyl, furanyl, pyranyl, pyridinyl, pyrrolyl,pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl,benzofuranyl, benzothiophenyl, benzothiopyranyl, benzimidazolyl,benzoxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl,benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl,purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl,carbazolyl, azepinyl, diazepinyl, acridinyl and the like, includingpartially hydrogenated derivatives thereof, each of which may beoptionally substituted. Preferred heteroaryl include indolyl, pyridinyl,pyrimidinyl, thienyl, furanyl pyrrolyl, imidazolyl and pyrazolyl, eachof which may be optionally substituted.

“Heteroarylalkyl” and “heteroaralkyl”, which may be usedinterchangeably, mean a radical-R^(a)R^(b) where R^(a) is an alkylenegroup and R^(b) is a heteroaryl group as defined herein

The terms “halo” and “halogen”, which may be used interchangeably, referto a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkylmoiety as defined herein. Examples of haloalkoxy moieties include, butare not limited to, trifluoromethoxy, difluoromethoxy,2,2,2-trifluoroethoxy, and the like.

“Hydroxyalkyl” refers to a subset of heteroalkyl and refers inparticular to an alkyl moiety as defined herein that is substituted withone or more, preferably one, two or three hydroxy groups, provided thatthe same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, optionally substitutedpiperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl,pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl,benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorpholinylsulfone, dihydroquinolinyl, dihydrisoquinolinyl,tetrahydroquinolinyl, tetrahydrisoquinolinyl, and the like.

“Optionally substituted”, when used in association with “aryl”, phenyl”,“heteroaryl” (including indolyl such as indol-1-yl, indol-2-yl andindol-3-yl, 2,3-dihydroindolyl such as 2,3-dihydroindol-1-yl,2,3-dihydroindol-2-yl and 2,3-dihydroindol-3-yl, indazolyl such asindazol-1-yl, indazol-2-yl and indazol-3-yl, benzimidazolyl such asbenzimidazol-1-yl and benzimidazol-2-yl, benzofuranyl such asbenzofuran-2-yl and benzofuran-3-yl, benzothiophenyl such asbenzothiophen-2-yl and benzothiophen-3-yl, benzoxazol-2-yl,benzothiazol-2-yl, thienyl, furanyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,imidazolyl, pyrazolyl and quinolinyl)” or “heterocyclyl”, means an aryl,phenyl, heteroaryl or heterocyclyl which is optionally substitutedindependently with one to four substituents, preferably one or twosubstituents selected from alkyl, cycloalkyl, alkoxy, halo, haloalkyl,haloalkoxy, cyano, nitro, heteroalkyl, amino, mono-alkylamino,di-alkylamino, hydroxyalkyl, alkoxyalkyl, alkylsulfonyl,alkylsulfonamido, benzyloxy, cycloalkylalkyl, cycloalkoxy,cycloalkylalkoxy, alkylsulfonyloxy, optionally substituted thienyl,optionally substituted pyrazolyl, optionally substituted pyridinyl,morpholinocarbonyl,—CH₂)_(q)S(O)_(r)R^(f); —(CH₂)_(q)—NR^(g)R^(h);—(CH₂)_(q)—C(═O)—NR^(g)R^(h); —CH₂)_(q)—C(═O)—C(═O)—NR^(g)R^(h);—CH₂)_(q)—SO₂—NR^(g)R^(h)d; —(CH₂)_(q)—N(R^(f))—C(═O)—R^(i);—(CH₂)_(q)—C(═O)—R^(i); or —CH₂)_(q)—N(R^(f))—SO₂—R^(g); where q is 0 or1, r is from 0 to 2, R^(f), R^(g), and R^(h) each independently ishydrogen or alkyl, and each R^(i) is independently hydrogen, alkyl,hydroxy, or alkoxy. Certain preferred optional substituents for “aryl”,phenyl”, “heteroaryl” “cycloalkyl” or “heterocyclyl” include alkyl,halo, haloalkyl, alkoxy, cyano, amino, aminosulfonyl, and alkylsulfonyl.More preferred substituents are methyl, fluoro, chloro, trifluoromethyl,methoxy, amino, aminosulfonyl and methanesulfonyl.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease” and “Disease state” means any disease, condition, symptom,disorder or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude:

acid addition salts formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid,benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid,ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid,glutamic acid, glycolic acid, hydroxynaphtoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,malonic acid, mandelic acid, methanesulfonic acid, muconic acid,2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinicacid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, andthe like; or

salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic or inorganicbase. Acceptable organic bases include diethanolamine, ethanolamine,N-methylglucamine, triethanolamine, tromethamine, and the like.Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

The preferred pharmaceutically acceptable salts are the salts formedfrom acetic acid, hydrochloric acid, sulphuric acid, methanesulfonicacid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium,potassium, calcium, zinc, and magnesium.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like.Skilled persons will know how to choose a group for the ease of removaland for the ability to withstand the following reactions.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂0, such combination beingable to form one or more hydrate.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Pain” and pain conditions (states) as used herein means pain associatedwith any of a wide variety of causes, including but not limited to,inflammatory pain, surgical pain, visceral pain, dental pain,premenstrual pain, central pain, pain due to burns, migraine or clusterheadaches, nerve injury, neuritis, neuralgias, poisoning, ischemicinjury, interstitial cystitis, cancer pain, viral, parasitic orbacterial infection, post-traumatic injuries (including fractures andsports injuries), and pain associated with functional bowel disorderssuch as irritable bowel syndrome.

“Inflammation” means any pathological process characterized by injury ordestruction of tissues resulting from cytologic reactions, chemicalreactions or other causes. Inflammation may be manifested by signs ofpain, heat, redness, swelling, and loss of function. Inflammationindications include, but are not limited to, bacterial, fungal or viralinfections, rheumatoid arthritis, osteoarthritis, surgery, bladderinfection or idiopathic bladder inflammation, over-use, old age, ornutritional deficiencies, prostatis and conjunctivitis.

“Cognition” means any mental process associated with acquiring andretaining knowledge. A “cognition disorder” means any disturbance to themental process or processes related to thinking, reasoning, judgment admemory. Cognition disorders may result from or other wise be associatedwith Parkinson's disease, Huntington's disease, anxiety, depression,manic depression, psychosis, epilepsy, obsessive compulsive disorders,mood disorders, migraine, Alzheimer's disease, sleep disorders, feedingdisorders such as anorexia, bulimia, and obesity, panic attacks,akathisia, attention deficit hyperactivity disorder (ADHD), attentiondeficit disorder (ADD), withdrawal from drug abuse such as cocaine,ethanol, nicotine and benzodiazepines, schizophrenia, and also disordersassociated with spinal trauma and/or head injury such as hydrocephalus.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as preferred, more preferred and most preferreddefinitions, if any.

“Treating” or “treatment” of a disease state includes:

-   -   (i) preventing the disease state, i.e. causing the clinical        symptoms of the disease state not to develop in a subject that        may be exposed to or predisposed to the disease state, but does        not yet experience or display symptoms of the disease state.    -   (ii) inhibiting the disease state, i.e., arresting the        development of the disease state or its clinical symptoms, or    -   (iii) relieving the disease state, i.e., causing temporary or        permanent regression of the disease state or its clinical        symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature and Structures

In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. Chemical structures shownherein were prepared using ISIS® version 2.2. Any open valency appearingon a carbon, oxygen, sulfur or nitrogen atom in the structures hereinindicates the presence of a hydrogen atom.

Whenever a chiral carbon is present in a chemical structure, it isintended that all stereoisomers associated with that chiral carbon areencompassed by the structure.

All patents and publications identified herein are incorporated hereinby reference in their entirety.

Compounds of the Invention

The invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Ar¹ and Ar² each independently is:        -   optionally substituted aryl; or        -   optionally substituted heteroaryl; and    -   R¹ and R² each independently is:        -   hydrogen;        -   fluoro;        -   C₁₋₆alkyl; or        -   halo-C₁₋₆alkyl.

In certain embodiments the compounds of the invention may be of formulaIa or Ib:

wherein Ar¹, Ar², R¹ and R² are as defined herein.

In certain embodiments of formula I, Ia or Ib, R¹ and R² are C₁₋₆alkyl.

In certain embodiments of formula I, Ia or Ib, Ar¹ and Ar² areoptionally substituted phenyl.

In certain embodiments of formula I, Ia or Ib, Ar¹ and A² are phenyl,each of which is optionally substituted with one, two or three groupseach independently selected from:

-   -   C₁₋₆alkyl;    -   halo;    -   C₁₋₆alkoxy;    -   halo-C₁₋₆alkoxy;    -   halo-C₁₋₆alkyl;    -   hetero-C₁₋₆alkyl;    -   cyano;    -   C₁₋₆alkyl-amino;    -   di-C₁₋₆alkyl-amino;    -   nitro; or    -   —(CR^(a)R^(b))_(m)—X—R³ wherein:        -   X is C(O) or S(O)_(n);        -   m is 0 or 1;        -   n is 0, 1 or2;        -   R^(a) and R^(b) each independently is:            -   hydrogen; or            -   C₁₋₆alkyl; and        -   R³ is:            -   hydrogen;            -   C₁₋₆alkyl;            -   C₁₋₆alkoxy;            -   hetero-C₁₋₆alkyl;            -   halo-C₁₋₆alkyl;            -   C₃₋₇cycloalkyl;            -   aryl;            -   heteroaryl;            -   heterocyclyl;            -   C₃₋₇cycloalkyl-C₁₋₆alkyl;            -   aryl-C₁₋₆alkyl;            -   heteroaryl-C₁₋₆alkyl;            -   heterocyclyl-C₁₋₆alkyl;            -   C₃₋₇cycloalkyloxy;            -   aryloxy;            -   heteroaryloxy;            -   heterocyclyloxy;            -   C₃₋₇cycloalkyloxy-C₁₋₆alkyl;            -   aryloxy-C₁₋₆alkyl;            -   heteroaryloxy-C₁₋₆alkyl;            -   heterocyclyloxy-C₁₋₆alkyl; or            -   —NR⁴R⁵, wherein:                -   R⁴ is:                -    hydrogen; or                -    C₁₋₆alkyl; and                -   R⁵ is:                -    hydrogen;                -    C₁₋₆alkyl;                -    hetero-C₁₋₆alkyl;                -    C₃₋₇cycloalkyl;                -    aryl;                -    heteroaryl;                -    heterocyclyl;                -    C₃₋₇cycloalkyl-C₁₋₆alkyl;                -    aryl-C₁₋₆alkyl;                -    heteroaryl-C₁₋₆alkyl; or                -    heterocyclyl-C₁₋₆alkyl.

In certain embodiments of formula I, Ia or Ib, Ar¹ and Ar² each arephenyl optionally substituted with one, two or three groups eachindependently selected from:

-   -   C₁₋₆alkyl;    -   halo;    -   C₁₋₆alkoxy;    -   halo-C₁₋₆alkoxy;    -   halo-C₁₋₆alkyl;    -   hetero-C₁₋₆alkyl;    -   cyano;    -   C₁₋₆alkyl-amino;    -   di-C₁₋₆alkyl-amino;    -   nitro; and    -   —(CR^(a)R^(b))_(m)—X—R³ wherein:        -   m is 0;        -   X is C(O) or S(O)_(n);        -   R³is —NR⁴R⁵, and            -   R⁴ and R⁵ each independently is:                -   hydrogen; or                -   C₁₋₆alkyl.

In certain embodiments of formula I, Ia or Ib, Ar¹ is phenyl optionallysubstituted with one, two or three groups each selected independentlyfrom halo, halo-C₁₋₆alkyl, C₁₋₆alkyl and C₁₋₆alkoxy.

In certain embodiments of formula I, Ia or Ib, Ar¹ is phenyl optionallysubstituted with one, two or three groups each selected independentlyfrom halo and C₁₋₆alkoxy.

In certain embodiments of formula I, Ia or Ib, Ar¹ is phenyl substitutedone, two or three times with a group or groups independently selectedfrom chloro, fluoro, methyl and methoxy.

In certain embodiments of formula I, Ia or Ib, Ar¹ is5-chloro-2-methoxy-phenyl, 5-chloro-2,4-dimethoxy-phenyl, phenyl,4-methoxy-phenyl, 4-methoxy-2-methyl-phenyl, 2,5-dimethoxy-phenyl,4-methoxy-phenyl, 4-chloro-phenyl, 3,4-dichloro-phenyl and3-chlorophenyl.

In certain embodiments of formula I, Ia or Ib, Ar¹ is4-trifluoromethyl-phenyl, 4-aminosulfonyl-phenyl, 4-N-methylamino-phenylor 4-N,N-dimethylamino-phenyl.

In certain embodiments of formula I, Ia or Ib, Ar¹ is phenyl substitutedonce or twice with methoxy and optionally substituted once with chloro.

In certain embodiments of formula I, Ia or Ib, Ar¹ is phenyl substitutedone, two or three times with a group or groups independently selectedfrom chloro and methoxy.

In certain embodiments of formula I, Ia or Ib, Ar¹ is5-chloro-2-methoxy-phenyl, 5-chloro-2,4-dimethoxy-phenyl, phenyl,4-methyl-phenyl, 2-methoxy-5-methyl-phenyl, 2-methyl-5-methoxy-phenyl,4-methoxy-2-methyl-phenyl, 2,5-dimethoxy-phenyl, 4-methoxy-phenyl,4-chloro-phenyl, 3,4-dichloro-phenyl, 3-chloro-phenyl, 2-methoxy-phenyl,4-tert-butyl-phenyl, 2,4-dimethoxy-phenyl, 3-trifluoromethyl-phenyl,4-methanesulfonyl-phenyl, 4-aminosulfonyl-phenyl,4-trifluoromethyl-phenyl, 5-fluoro-2-methoxy-phenyl,2-methoxy-5-trifluoromethyl-phenyl, 2-methoxy-5-tert-butyl-phenyl,4-chloro-2-methoxy-phenyl, 2,4,5-trimethoxy-phenyl,2,6-dimethoxy-phenyl, or 2,3-dimethoxy-phenyl.

In certain embodiments of formula I, Ia or Ib, Ar¹ is optionallysubstituted heteroaryl. Preferred heteroaryl include pyridinyl,pyrimidinyl, thienyl, furanyl, thiazolyl, oxazolyl, isothiazolyl andisoxaloyl, each of which may be optionally substituted with one or twogroups each selected independently from halo, C₁₋₆alkyl and C₁₋₆alkoxy.

In certain embodiments of formula I, Ia or Ib, Ar¹ is pyridinyl orisoxaloyl, each of which may be optionally substituted with one or twogroups each selected independently from halo, methyl and methoxy.

In certain embodiments of formula I, Ia or Ib, Ar² is phenyl optionallysubstituted once at the 4-position with halo, C₁₋₆alkyl, cyano,halo-C₁₋₆alkyl, C₁₋₆alkoxy or —(CR^(a)R^(b))_(m)—X—R³ wherein:

-   -   m is 0;    -   X is —SO₂—;    -   R³ is C₁₋₆alkyl or —NR⁴R⁵, and        -   R⁴ and R⁵ each independently is:            -   hydrogen; or            -   C₁₋₆alkyl.

In certain embodiments of formula I, Ia or Ib, Ar² is phenyl substitutedat the 4-position with cyano, —SO₂—NR⁵R⁶, or —SO₂—CH₃.

In certain embodiments of formula I, Ia or Ib, Ar² is phenyl substitutedat the 4-position with —SO₂—NR⁵R⁶.

In certain embodiments of formula I, Ia or Ib, Ar² is phenyl substitutedat the 4-position with —SO₂NH₂ or —SO₂—CH₃.

In certain embodiments of formula I, Ia or Ib, Ar² is phenyl substitutedat the 4-position with —SO₂NH₂.

In certain embodiments of formula I, Ia or Ib, Ar² is phenyl substitutedat the 4-position with —SO₂CH₃.

In certain embodiments of formula I, Ia or Ib, Ar² is phenyl,4-aminosulfonyl-phenyl, 4-methylaminosulfonyl-phenyl,4-dimethylaminosulfonyl-phenyl, 4-trifluoromethyl-phenyl,4-methyl-phenyl, 4-chloro-phenyl, 4-methanesulfonyl-phenyl,4-methoxy-phenyl, 4-cyano-phenyl or 4-bromo-phenyl.

In certain embodiments of formula I, Ia or Ib, R¹ and R² are C₁₋₆alkyl.

In certain embodiments of formula I, Ia or Ib, one of R¹ and R² ishydrogen and the other is C₁₋₆alkyl.

In certain embodiments of formula I, Ia or Ib, one of R¹ and R² ishydrogen and the other is methyl or ethyl.

In certain embodiments of formula I, Ia or Ib, R¹ and R² are methyl.

In certain embodiments of formula I, Ia or Ib, R¹ and R² are hydrogen.

In certain embodiments of the invention, the subject compounds are offormula II:

wherein:

-   -   p and q each independently is from 0 to 3;    -   R¹ and R² are C₁₋₆alkyl; and    -   R⁶ and R⁷ each independently is:        -   C₁₋₆alkyl;        -   halo;        -   C₁₋₆alkoxy;        -   halo-C₁₋₆alkoxy;        -   halo-C₁₋₆alkyl;        -   hetero-C₁₋₆alkyl;    -   cyano;    -   C₁₋₆alkyl-amino;        -   di-C₁₋₆alkyl-amino;        -   nitro; and        -   —(CR^(a)R^(b))_(m)—X—R³ wherein:            -   m is 0;            -   X is —SO₂—;            -   R³ is C₁₋₆alkyl or —NR⁴R⁵, and                -   R⁴ and R⁵ each independently is:                -    hydrogen; or                -    C₁₋₆alkyl.

In certain embodiments the compounds of the invention may be of formulaIIa or IIb:

wherein p, q, R¹, R², R⁶ and R⁷ are as defined herein.

In certain embodiments of formula II, IIa or IIb, R¹ and R² are methyl.

In certain embodiments of formula II, IIa or IIb, one of R¹ and R² ishydrogen and the other is methyl or ethyl.

In certain embodiments of formula II, IIa or IIb, R¹ and R² arehydrogen.

In certain embodiments of formula II, IIa or IIb, p is from 0 to 3 andeach R⁶ is independently:

-   -   C₁₋₆alkyl;    -   halo;    -   C₁₋₆alkoxy;    -   halo-C₁₋₆alkoxy;

halo-C₁₋₆alkyl;

-   -   hetero-C₁₋₆alkyl;    -   cyano;    -   C₁₋₆alkyl-amino;    -   di-C₁₋₆alkyl-amino;    -   nitro; and    -   —(CR^(a)R^(b))_(m)—X—R³ wherein:        -   m is 0;        -   X is —SO₂—;        -   R³ is C₁₋₆alkyl or —NR⁴R⁵, and            -   R⁴ and R⁵ each independently is:                -   hydrogen; or                -   C₁₋₆alkyl.

In certain embodiments of formula II, IIa or IIb, q is 1 and R⁷ is:

-   -   C₁₋₆alkyl;    -   halo;    -   C₁₋₆alkoxy;    -   halo-C₁₋₆alkoxy;    -   halo-C₁₋₆alkyl;    -   hetero-C₁₋₆alkyl;    -   cyano;    -   C₁₋₆alkyl-amino;    -   di-C₁₋₆alkyl-amino;    -   nitro; and    -   —(CR^(a)R^(b))_(m)—X—R³ wherein:        -   m is 0;        -   X is —13 SO₂—;        -   R³ is C₁₋₆alkyl or —NR⁴R⁵, and            -   R⁴ and R⁵ each independently is:                -   hydrogen; or                -   C₁₋₆alkyl.

In certain embodiments of formula II, IIa or IIb, p is from 1 to 3 andeach R⁶ is independently:

-   -   C₁₋₆alkyl;    -   halo;    -   C₁₋₆alkoxy;    -   halo-C₁₋₆alkoxy; or    -   halo-C₁₋₆alkyl.

In certain embodiments of formula II, IIa or IIb, p is from 1 to 3 andeach R⁶ is independently methyl, fluoro, chloro, methoxy ortrifluoromethyl.

In certain embodiments of formula II, IIa or IIb, p is from 1 to 3 andeach R⁶ is independently chloro or methoxy.

In certain embodiments of formula II, IIa or IIb, q is 1 and R⁷ is halo,cyano;, C₁₋₆alkyl, halo-C₁₋₆alkyl C₁₋₆alkoxy; or —(CR^(a)R^(b))_(m)—X—R³wherein:

-   -   m is 0;    -   X is —SO₂—;    -   R³ is C₁₋₆alkyl or —NR⁴R⁵, and        -   R⁴ and R⁵ each independently is:            -   hydrogen; or            -   C₁₋₆alkyl.

In certain embodiments of formula II, IIa or IIb, q is one and R⁷is atthe 4-position of the phenyl ring.

In certain embodiments of formula II, IIa or IIb, q is 1 and R⁷ is—SO₂NR⁴R⁵.

In certain embodiments of formula II, IIa or IIb, q is 1 and R⁷ is—SO₂NH₂.

In certain embodiments of the invention, the subject compounds are offormula III:

wherein:

-   -   p is from 0 to 3;    -   each R⁶ is independently selected from:        -   C₁₋₆alkyl;        -   halo;        -   C₁₋₆alkoxy;        -   halo-C₁₋₆alkoxy; or        -   halo-C₁₋₆alkyl; and    -   R⁷is:        -   halo;        -   cyano;        -   C₁₋₆alkyl;        -   C₁₋₆alkoxy; or        -   —(CR^(a)R^(b))_(m)—X—R³ wherein:            -   m is 0;            -   X is —SO₂—;            -   R³is C₁₋₆alkyl or —NR⁴R⁵, and            -   R⁴ and R⁵ each independently is:                -   hydrogen; or                -   C₁₋₆alkyl.

In certain embodiments the subject compounds may be of formula IIIa orIIIb:

wherein p, R⁶ and R⁷ are as defined herein.

In certain embodiments of formula III, IIIa or IIIb, p is from 0 to 3and each R⁶ is independently:

-   -   C₁₋₆alkyl;    -   halo;    -   C₁₋₆alkoxy;    -   halo-C₁₋₆alkoxy;    -   halo-C₁₋₆alkyl;    -   hetero-C₁₋₆alkyl;    -   cyano;    -   C₁₋₆alkyl-amino;    -   di-C₁₋₆alkyl-amino;    -   nitro; and    -   —(CR^(a)R^(b))_(m)—X—R³ wherein:        -   m is 0;        -   X is —SO₂—;        -   R³ is C₁₋₆alkyl or —NR⁴R⁵, and            -   R⁴ and R⁵ each independently is:                -   hydrogen; or                -   C₁₋₆alkyl.

In certain embodiments of formula III, IIIa or IIIb, p is from 1 to 3and each R⁶ is independently:

-   -   C₁₋₆alkyl;    -   halo;    -   C₁₋₆alkoxy;    -   halo-C₁₋₆alkoxy; or    -   halo-C₁₋₆alkyl.

In certain embodiments of formula III, IIIa or IIIb, p is from 1 to 3and each R⁶ is independently methyl, fluoro, chloro, methoxy ortrifluoromethyl.

In certain embodiments of formula III, IIIa or IIIb, p is 2 or 3 andeach R⁶ is independently chloro or methoxy.

In certain embodiments of formula III, IIIa or IIIb, R⁷ is—(CR^(a)R^(b))_(m)—X—R³ wherein:

-   -   m is 0;        -   X is —SO₂—;    -   R³ is C₁₋₆alkyl or —NR⁴R⁵, and        -   R⁴ and R⁵ each independently is:            -   hydrogen; or            -   C₁₋₆alkyl.

In certain embodiments of formula III, IIIa or IIIb, R⁷ is —SO₂NR⁵R⁶.

In certain embodiments of formula III, IIIa or IIIb, R⁷ is —SO₂NH₂.

Where any of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R^(a) or R^(b) herein are alkylor contain an alkyl moiety, such alkyl is preferably lower alkyl, i.e.C₁-C₆alkyl, and more preferably C₁-C₄alkyl.

Representative compounds in accordance with the methods of the inventionare shown in Table 1. Compounds identified as “cis” or “trans” wereisolated as racemates.

TABLE 1 # Structure Name MP/M + H 1

5-Chloro-N-[cis-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide220-222° C. 2

5-Chloro-N-[trans-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide203-204° C. 3

5-Chloro-N-[(1R,3S)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide 99.9-103.3° C. 4

5-Chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide 96.8-101.1° C. 5

5-Chloro-N-[3-(4-dimethylsulfamoyl-phenyl)-trans-2,2-dimethyl-cyclopropyl]-2-methoxy-benzamide437 6

5-Chloro-N-[trans-2,2-dimethyl-3-(4-trifluoromethyl-phenyl)-cyclopropyl]-2-methoxy-benzamide398 7

5-Chloro-N-[trans-2,2-dimethyl-3-phenyl-cyclopropyl]-2-methoxy-benzamide330 8

5-Chloro-N-[trans-2,2-dimethyl-3-(4-trifluoromethyl-phenyl)-cyclopropyl]-2,4-dimethoxy-benzamide428 9

5-Chloro-N-[trans-2,2-dimethyl-3-p-tolyl-cyclopropyl]-2-methoxy-benzamide344 10

5-Chloro-N-[trans-2,2-dimethyl-3-p-tolyl-cyclopropyl]-2,4-dimethoxy-benzamide148.3-150.9° C. 11

5-Chloro-N-[3-(4-chloro-phenyl)-trans-2,2-dimethyl-cyclopropyl]-2,4-dimethoxy-benzamide166.4-167.3° C. 12

5-Chloro-N-[3-(4-chloro-phenyl)-trans-2,2-dimethyl-cyclopropyl]-2-methoxy-benzamide365 13

5-Chloro-N-[3-(4-methanesulfonyl-phenyl)-trans-2,2-dimethyl-cyclopropyl]-2-methoxy-benzamide408 14

5-Chloro-N-[trans-2,2-dimethyl-3-phenyl-cyclopropyl]-2,4-dimethoxy-benzamide360 15

N-[(Trans-2,2-Dimethyl-3-p-tolyl-cyclopropyl]-benzamide 280 16

N-[trans-2,2-Dimethyl-3-p-tolyl-cyclopropyl]-4-methyl-benzamide 294 17

N-[trans-2,2-Dimethyl-3-p-tolyl-cyclopropyl]-2-methoxy-5-methyl-benzamide324 18

N-[trans-2,2-Dimethyl-3-p-tolyl-cyclopropyl]-4-methoxy-2-methyl-benzamide324 19

N-[trans-2,2-Dimethyl-3-p-tolyl-cyclopropyl]-2,5-dimethoxy-benzamide 34020

N-[trans-2,2-Dimethyl-3-p-tolyl-cyclopropyl]-4-methoxy-benzamide 310 21

4-Chloro-N-[trans-2,2-dimethyl-3-p-tolyl-cyclopropyl]-benzamide 314 22

3,4-Dichloro-N-[(trans-2,2-dimethyl-3-p-tolyl-cyclopropyl]-benzamide 34923

N-[3-(4-Chloro-phenyl)-trans-2,2-dimethyl-cyclopropyl]-2-methoxy-5-methyl-benzamide344 24

N-[3-(4-Chloro-phenyl)-trans-2,2-dimethyl-cyclopropyl]-4-methoxy-2-methyl-benzamide344 25

5-Chloro-2,4-dimethoxy-N-[3-(4-methoxy-phenyl)-trans-2,2-dimethyl-cyclopropyl]-benzamide390 26

5-Chloro-2-methoxy-N-[3-(4-methoxy-phenyl)-trans-2,2-dimethyl-cyclopropyl]-benzamide360 27

2-Methoxy-N-[3-(4-methoxy-phenyl)-trans-2,2-dimethyl-cyclopropyl]-5-methyl-benzamide340 28

4-Methoxy-N-[3-(4-methoxy-phenyl)-trans-2,2-dimethyl-cyclopropyl]-2-methyl-benzamide340 29

2,5-Dimethoxy-N-[3-(4-methoxy-phenyl)-trans-2,2-dimethyl-cyclopropyl]-benzamide356 30

N-[3-(4-Chloro-phenyl)-trans-2,2-dimethyl-cyclopropyl]-4-methyl-benzamide314 31

N-[3-(4-Chloro-phenyl)-trans-2,2-dimethyl-cyclopropyl]-benzamide 300 32

3,4-Dichloro-N-[3-(4-chloro-phenyl)-trans-2,2-dimethyl-cyclopropyl]-benzamide369 33

4-Chloro-N-[3-(4-chloro-phenyl)-trans-2,2-dimethyl-cyclopropyl]-benzamide335 34

N-[3-(4-Chloro-phenyl)-trans-2,2-dimethyl-cyclopropyl]-4-methoxy-benzamide330 35

N-[3-(4-Methoxy-phenyl)-trans-2,2-dimethyl-cyclopropyl]-4-methyl-benzamide310 36

N-[3-(4-Methoxy-phenyl)-trans-2,2-dimethyl-cyclopropyl]-benzamide 296 37

3,4-Dichloro-N-[3-(4-methoxy-phenyl)-trans-2,2-dimethyl-cyclopropyl]-benzamide365 38

4-Chloro-N-[3-(4-methoxy-phenyl)-trans-2,2-dimethyl-cyclopropyl]-benzamide330 39

4-Methoxy-N-[3-(4-methoxy-phenyl)-trans-2,2-dimethyl-cyclopropyl]-benzamide326 40

5-Chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-methylsulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide423 41

5-Chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2,4-dimethoxy-benzamide439 42

5-Chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-methylsulfamoyl-phenyl)-cyclopropyl]-2,4-dimethoxy-benzamide453 43

5-Chloro-N-[3-(4-methanesulfonyl-phenyl)-(1S,3R)-2,2-dimethyl-cyclopropyl]-2-methoxy-benzamide408 44

5-Chloro-N-[trans-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2,4-dimethoxy-benzamide439 45

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-4-methyl-benzamide359 46

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-benzamide 34547

4-Chloro-N-[trans-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-benzamide379 48

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-4-methoxy-benzamide375 49

3-Chloro-N-[trans-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-benzamide379 50

N-[trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide375 51

4-tert-Butyl-N-[trans-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-benzamide401 52

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-4-methoxy-2-methyl-benzamide389 53

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2,4-dimethoxy-benzamide405 54

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-3-trifluoromethyl-benzamide413 55

3,4-Dichloro-N-[trans-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-benzamide414 56

5-Chloro-2-methoxy-N-(trans-2-phenyl-cyclopropyl)-benzamide 302 57

5-Chloro-2,4-dimethoxy-N-(trans-2-phenyl-cyclopropyl)-benzamide 302 58

N-(Trans-2,2-Dimethyl-3-phenyl-cyclopropyl)-4-methanesulfonyl-benzamide344 59

N-(Trans-2,2-Dimethyl-3-phenyl-cyclopropyl)-4-sulfamoyl-benzamide 345 60

5-Chloro-2,4-dimethoxy-N-[trans-2-(4-sulfamoyl-phenyl)-cyclopropyl]-benzamide411 61

5-Chloro-2-methoxy-N-[trans-2-(4-sulfamoyl-phenyl)-cyclopropyl]-benzamide381 62

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-4-trifluoromethyl-benzamide413 63

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2,5-dimethoxy-benzamide405 64

5-Chloro-2-methoxy-N-[trans-2-methyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-benzamide395 65

5-Chloro-N-[trans-2-ethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide409 66

5-Methyl-isoxazole-3-carboxylicacid[trans-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-amide 350 67

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-5-fluoro-2-methoxy-benzamide172.6-173.6° C. 68

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-5-methoxy-2-methyl-benzamide 99-100° C. 69

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-nicotinamide346 70

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2,3,5-trimethoxy-benzamide144-145° C. 71

N-[(1S,3R)-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2,4-dimethoxy-benzamide405 72

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-5-trifluoromethyl-benzamide443 73

5-tert-Butyl-N-[trans-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide431 74

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2,4-dimethoxy-5-methyl-benzamide419 75

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-4-methyl-benzamide389 76

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2,6-dimethoxy-nicotinamide406 77

N-[(1S,3R)-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-5-fluoro-2-methoxy-benzamide164-165° C. 78

5-Chloro-2-methoxy-N-[trans-3-(3-methoxy-4-sulfamoyl-phenyl)-2,2-dimethyl-cyclopropyl]-benzamide193-194° C. 79

5-Chloro-N-[trans-3-(4-cyano-phenyl)-2,2-dimethyl-cyclopropyl]-2-methoxy-benzamide157.2-157.6° C. 80

N-[Trans-3-(4-Bromo-phenyl)-2,2-dimethyl-cyclopropyl]-5-chloro-2-methoxy-benzamide125.5-126.9° C. 81

4-Chloro-N-[trans-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide409 82

5-Chloro-N-[2(trans-2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-nicotinamide410 83

5-Chloro-N-[trans-3-(4-methanesulfonyl-phenyl)-2,2-dimethyl-cylopropyl]-2,4-dimethoxy-benzamide438 84

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2,4,5-trimethoxy-benzamide435 85

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2,6-dimethoxy-benzamide405 86

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-nicotinamide376 87

N-[Trans-3-(4-Methanesulfonyl-phenyl)-2,2-dimethyl-cyclopropyl]-2,4-dimethoxy-benzamide404 88

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2,3-dimethoxy-benzamide405 89

N-[Trans-2,2-Dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-3-trifluoromethyl-benzamide413 90

N-[Trans-3-(4-Chloro-phenyl)-2,2-dimethyl-cyclopropyl]-nicotinamide 30191

2′-Methoxy-biphenyl-3-carboxylicacid[trans-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-amide 451 92

5-Chloro-2-methoxy-N-[trans-3-(3-methoxy-phenyl)-2,2-dimethyl-cyclopropyl]-benzamide360 93

N-[Trans-2,2-Dimethyl-3-(3-trifluoromethyl-phenyl)-cyclopropyl]-4-methanesulfonyl-benzamide412 94

N-[(1S,3R)-3-(4-Methanesulfonyl-phenyl)-2,2-dimethyl-cyclopropyl]-2,6-dimethoxy-nicotinamide405

Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 1-40. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78 ° C. to about150 ° C., more preferably from about 0 ° C. to about 125 ° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20 ° C.

Scheme A below illustrates one synthetic procedure usable to preparecompounds of the invention, wherein R is lower alkyl, X is hydroxy, haloor alkoxy, and Ar¹, Ar², R¹, and R² are as defined herein.

In Scheme A, aryl aldehyde compound a is reacted with cyano estercompound b to afford an arylonitrile ester compound c. This reaction maybe carried out in the presence of amine base catalyst. Compound c istreated with nitro compound d step 2 to provide cyclopropyl nitrileester compound e. In step 3 nitrile ester compound e is hydrolized underbasic conditions to give cyclopropyl nitrile acid compound f In step 4compound f is heated in the presence of base to afford cyclopropylnitrile compound g. Nitrile compound g is then converted to cyclopropylamide compound h in step 5 by treatment of compound g with hydrogenperoxide in the presence of base. In step 6 cyclopropyl amide compoundis treated with bromine and NaOH or like base to afford cyclopropylamine compound i. Amine compound i then undergoes an amide couplingreaction with acid compound j in step 7 to yield compound k, which is acompound of formula I in accordance with the invention.

Numerous variations on the procedures of Scheme A are possible and willbe readily apparent to those skilled in the art. For example, nitrilecompound g may be hydrolized directly to a carboxylic acid compound instep 5, and then treated with ethyl chloroformate followed by azide toform compound i. The amide formation of step 7 may utilize acarbodiimide such as dicyclohexylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide or otherdiimide as used in conventional amide coupling reactions. Desiredstereochemistry may be introduced by selection of appropriate startingmaterials and/or use of chiral separation techniques. The amine compoundi in many embodiments may undergo chromatographic chiral resolution toprovide specific enantiomers.

Scheme B below illustrates another synthetic procedure for the compoundsof the invention, wherein R is lower alkyl (preferably methyl), X ishydroxy, halo or alkoxy, and Ar¹, Ar², R¹, and R² are as defined herein.

In step 1 of Scheme B, amide compound m is treated with trifluoroaceticanhydride, followed by styryl compound n, to afford cyclobutanonecompound o. In step 2, cyclobutanone o is treated with Lithiumbis(trimethylsilyl)amide, followed by n-bromo-succinimide or likebrominating agent, then acid, and then base, to afford cyclopropyl acidcompound p. Cyclopropyl compound p is converted to amine q in step 3 bytreatment with chloroformate ester, followed by sodium azide andacidification. In step 4 cyclopropylamine q is subject to amide couplingwith compound i to afford cyclopropyl amide r, which is a compound offormula I in accordance with the invention.

Scheme C shows yet another synthetic route to the compounds of theinvention, wherein R is lower alkyl, and Ar¹, Ar², R¹, and R² are asdefined herein.

In step 1 of Scheme C, cinnamate ester compound s is reacted with Wittigreagent t to effect a cyclization reaction and provide cyclopyl estercompound u. Diazomethane may be used in place of Wittig reagent t toprepare compounds where R¹ and R² are hydrogen. Cyclopropyl ester u ishydrolized to cyclopropyl acid compound p. Compound p is then convertedto an amine q in step 3 and undergoes amide coupling in step 4,following the same procedure of Scheme B, to afford cyclopropyl amide r.

Specific details for producing compounds of the invention are describedin the Examples section below.

Utility

The compounds of the invention are usable for the treatment of diseasesor conditions associated with the nicotinic alpha 7 (α7nACh) receptor,including treatment of psychotic diseases, neurodegenerative diseases,and cognitive impairments involving a dysfunction of the cholinergicsystem, and conditions of memory and/or cognition impairment, including,for example, schizophrenia, anxiety, mania, depression, manicdepression, Tourette's syndrome, Parkinson's disease, Huntington'sdisease, cognitive disorders (such as Alzheimer's disease, Lewy BodyDementia, Amyotrophic Lateral Sclerosis, memory impairment, memory loss,cognition deficit, attention deficit, Attention Deficit HyperactivityDisorder), and other uses such as treatment of nicotine addiction,inducing smoking cessation, treating pain (i.e., analgesic use),providing neuroprotection, and treating jetlag.

The compounds of the invention are useful for enhancing or improvingcognition in Alzheimer's patients and patients having cognitionimpairment or cognitive disorders associated with schizophrenia,anxiety, mania, depression, manic depression, Tourette's syndrome,Parkinson's disease, Huntington's disease, Lewy Body Dementia,Amyotrophic Lateral Sclerosis, memory impairment, memory loss, cognitiondeficit, attention deficit or Attention Deficit Hyperactivity Disorder.

Thus, the invention provides a method of treating a patient or subject,specifically a mammal and especially a human, suffering from psychoticdiseases, neurodegenerative diseases involving a dysfunction of thecholinergic system, and conditions of memory and/or cognitionimpairment, including, for example, schizophrenia, anxiety, mania,depression, manic depression [examples of psychotic disorders],Tourette's syndrome, Parkinson's disease, Huntington's disease [examplesof neurodegenerative diseases], and/or cognitive disorders (such asAlzheimer's disease, Lewy Body Dementia, Amyotrophic Lateral Sclerosis,memory impairment, memory loss, cognition deficit, attention deficit,Attention Deficit Hyperactivity Disorder) comprising administering tothe patient an effective amount of a compound of the invention.

Neurodegenerative disorders include, but are not limited to, treatmentand/or prophylaxis of Alzheimer's diseases, Pick's disease, diffuse LewyBody disease, progressive supranuclear palsy (Steel-Richardsonsyndrome), multisystem degeneration (Shy-Drager syndrome), motor neurondiseases including amyotrophic lateral sclerosis, degenerative ataxias,cortical basal degeneration, ALS-Parkinson's-Dementia complex of Guam,subacute sclerosing panencephalitis, Huntington's disease, Parkinson'sdisease, synucleinopathies, primary progressive aphasia, striatonigraldegeneration, Machado-Joseph disease/spinocerebellar ataxia type 3,olivopontocerebellar degenerations, Gilles De La Tourette's disease,bulbar, pseudobulbar palsy, spinal muscular atrophy, spinobulbarmuscular atrophy (Kennedy's disease), primary lateral sclerosis,familial spastic paraplegia, Werdnig-Hoffmann disease,Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease,familial spastic disease, Wohlfart-Kugelberg-Welander disease, spasticparaparesis, progressive multifocal leukoencephalopathy, prion diseases(such as Creutzfeldt-Jakob, Gerstmann-Sträussler-Scheinker disease, Kuruand fatal familial insomnia), and neurodegenerative disorders resultingfrom cerebral ischemia or infarction including embolic occlusion andthrombotic occlusion as well as intracranial hemorrhage of any type(including, but not limited to, epidural, subdural, subarachnoid andintracerebral), and intracranial and intravertebral lesions (including,but not limited to, contusion, penetration, shear, compression andlaceration).

In addition, the compounds of the invention may be used to treatage-related dementia and other dementias and conditions with memory lossincluding age-related memory loss, senility, vascular dementia, diffusewhite matter disease (Binswanger's disease), dementia of endocrine ormetabolic origin, dementia of head trauma and diffuse brain damage,dementia pugilistica and frontal lobe dementia. Thus, the inventionprovides a method of treating a patient, especially a human, sufferingfrom age-related dementia and other dementias and conditions with memoryloss, as well as enhancing cognitive memory in Alzheimer's patients,comprising administering to the patient an effective amount of acompound of the invention.

The invention provides methods of treating subjects suffering frommemory impairment due to, for example, Alzheimer's disease, mildcognitive impairment due to aging, schizophrenia, Parkinson's disease,Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease,depression, aging, head trauma, stroke, CNS hypoxia, cerebral senility,multiinfarct dementia and other neurological conditions, as well as HIVand cardiovascular diseases, comprising administering an effectiveamount of a compound of the invention.

Amyloid precursor protein (APP) and Aβ peptides derived therefrom, e.g.,Aβ₁₋₄₀, Aβ₁₋₄₂, and other fragments, are known to be involved in thepathology of Alzheimer's disease. The Aβ₁₋₄₂ peptides are not onlyimplicated in neurotoxicity but also are known to inhibit cholinergictransmitter function. Further, it has been determined that Aβ peptidesbind to α7nACh receptors. Agents which block the binding of the Aβpeptides to α-7 nAChRs are thus useful for treating neurodegenerativediseases. In addition, stimulation α7nACh receptors can protect neuronsagainst cytotoxicity associated with Aβ peptides. Thus, the inventionprovides a method of treating and/or preventing dementia in anAlzheimer's patient which comprises administering to the subject atherapeutically effective amount of a compound according to FormulasI-IV to inhibit the binding of an amyloid beta peptide (preferably,Aβ₁₋₄₂) with nACh receptors, preferable α7nACh receptors, mostpreferably, human α7nACh receptors (as well as a method for treatingand/or preventing other clinical manifestations of Alzheimer's diseasethat include, but are not limited to, cognitive and language deficits,apraxias, depression, delusions and other neuropsychiatric symptoms andsigns, and movement and gait abnormalities).

The invention also provides methods for treating other amyloidosisdiseases, for example, hereditary cerebral angiopathy, nonneuropathichereditary amyloid, Down's syndrome, macroglobulinemia, secondaryfamilial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma,pancreatic- and cardiac-related amyloidosis, chronic hemodialysisanthropathy, and Finnish and Iowa amyloidosis.

Nicotinic receptors have been implicated as playing a role in the body'sresponse to alcohol ingestion, and the compounds of the invention areuseful in the treatment of alcohol withdrawal and in anti-intoxicationtherapy.

Agonists for the α7nACh receptor subtypes can also be used forneuroprotection against damage associated with strokes and ischemia andglutamate-induced excitotoxicity, and the invention thus provides amethod of treating a patient to provide for neuroprotection againstdamage associated with strokes and ischemia and glutamate-inducedexcitotoxicity comprising administering to the patient an effectiveamount of a compound of the invention.

Agonists for the α7nACh receptor subtypes can also be used in thetreatment of nicotine addiction, inducing smoking cessation, treatingpain, and treating jetlag, obesity, diabetes, and inflammation, and theinvention thus provides a method of treating a patient suffering fromnicotine addiction, pain, jetlag, obesity, diabetes, and/orinflammation, or a method of inducing smoking cessation in a patientcomprising administering to the patient an effective amount of acompound of the invention

The inflammatory reflex is an autonomic nervous system response to aninflammatory signal. Upon sensing an inflammatory stimulus, theautonomic nervous system responds through the vagus nerve by releasingacetylcholine and activating nicotinic α7 receptors on macrophages.These macrophages in turn release cytokines. Dysfunctions in thispathway have been linked to human inflammatory diseases includingrheumatoid arthritis, diabetes and sepsis. Macrophages express thenicotinic α7 receptor and it is likely this receptor that mediates thecholinergic anti-inflammatory response. Therefore, compounds of theinvention may be useful for treating a patient (e.g., a mammal, such asa human) suffering from an inflammatory disease or disorder, such as,but not limited to, rheumatoid arthritis, diabetes or sepsis.

The compounds of the invention are expected to find utility asanalgesics in the treatment of diseases and conditions associated withpain from a wide variety of causes, including, but not limited to,inflammatory pain, surgical pain, visceral pain, dental pain,premenstrual pain, central pain, pain due to burns, migraine or clusterheadaches, nerve injury, neuritis, neuralgias, poisoning, ischemicinjury, interstitial cystitis, cancer pain, viral, parasitic orbacterial infection, post-traumatic injuries (including fractures andsports injuries), and pain associated with functional bowel disorderssuch as irritable bowel syndrome.

Further, compounds of the invention are useful for treating respiratorydisorders, including chronic obstructive pulmonary disorder (COPD),asthma, bronchospasm, and the like.

In addition, due to their affinity to α7nACh receptors, labeledderivatives of the compounds of Formulas I-IV (e.g., C¹¹ or F¹⁸ labeledderivatives), can be used in neuroimaging of the receptors within, e.g.,the brain. Thus, using such labeled agents in vivo imaging of thereceptors can be performed using, e.g., PET imaging.

The invention also provides a method of treating a patient sufferingfrom, for example, mild cognitive impairment (MCI), vascular dementia(VaD), age-associated cognitive decline (AACD), amnesia associatedw/open-heart-surgery, cardiac arrest, and/or general anesthesia, memorydeficits from early exposure of anesthetic agents, sleep deprivationinduced cognitive impairment, chronic fatigue syndrome, narcolepsy,AIDS-related dementia, epilepsy-related cognitive impairment, Down'ssyndrome, Alcoholism related dementia, drug/substance induced memoryimpairments, Dementia Puglistica (Boxer Syndrome), and animal dementia(e.g., dogs, cats, horses, etc.) comprising administering to the patientan effective amount of a compound of the invention.

Administration and Pharmaceutical Composition

The invention includes pharmaceutical compositions comprising at leastone compound of the present invention, or an individual isomer, racemicor non-racemic mixture of isomers or a pharmaceutically acceptable saltor solvate thereof, together with at least one pharmaceuticallyacceptable carrier, and optionally other therapeutic and/or prophylacticingredients.

In general, the compounds of the invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this Application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

Compounds of the invention may be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral(including intramuscular, intraarterial, intrathecal, subcutaneous andintravenous) administration or in a form suitable for administration byinhalation or insufflation. The preferred manner of administration isgenerally oral using a convenient daily dosage regimen which can beadjusted according to the degree of affliction.

A compound or compounds of the invention, together with one or moreconventional adjuvants, carriers, or diluents, may be placed into theform of pharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the invention may be formulated in a wide variety oforal administration dosage forms. The pharmaceutical compositions anddosage forms may comprise a compound or compounds of the presentinvention or pharmaceutically acceptable salts thereof as the activecomponent. The pharmaceutically acceptable carriers may be either solidor liquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier may be one or more substances which may also act as diluents,flavouring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial. In powders, the carrier generally is a finely divided solidwhich is a mixture with the finely divided active component. In tablets,the active component generally is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired. The powders and tablets preferably contain fromabout one (1) to about seventy (70) percent of the active compound.Suitable carriers include but are not limited to magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier, providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges maybe as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable. organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration assuppositories. A low melting wax, such as a mixture of fatty acidglycerides or cocoa butter is first melted and the active component isdispersed homogeneously, for example, by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and to solidify.

The compounds of the invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. Thesolutions or suspensions are applied directly to the nasal cavity byconventional means, for example, with a dropper, pipette or spray. Theformulations may be provided in a single or multidose form. In thelatter case of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

The compounds of the invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to a skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described below.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof. The following abbreviations may be used in the Examples.

ABBREVIATIONS

DCM dichloromethane/methylene chloride

DMF N,N-dimethylformamide

DMAP 4-dimethylaminopyridine

EDC-MeI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide

EtOAc ethyl acetate

EtOH ethanol

tBuOH tert-butanol

gc gas chromatography

HMPA hexamethylphosphoramide

hplc high performance liquid chromatography

mCPBA m-chloroperbenzoic acid

MeCN acetonitrile

NMP N-methyl pyrrolidinone

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

LDA lithium diisopropylamine

LHMDS Lithium bis(trimethylsilyl)amide

TBAF tetrabutylammonium fluoride

TLC thin layer chromatography

Preparation 1 2,2-Dimethyl-3-phenyl-cyclopropanecarbonitrile

The synthetic procedure described in this Preparation was carried outaccording to the process shown in Scheme D.

Step 1 (E)-2-Cyano-3-phenyl-acrylic acid ethyl ester

A mixture of benzaldehyde (0.6 mol, 63.7 g), ethyl cyanoacetate (0.6mol, 67.8 g) and piperidine (1 mL) in EtOH (60 mL) was stirredovernight. The clear solution was then placed in an ice-water bath toinitiate the crystallization. The crystalline material was filtered,washed with EtOH and dried in a vacuum oven at 50° C. to give 58.27 g of(E)-2-cyano-3-phenyl-acrylic acid ethyl ester. The mother liquors andthe washings were concentrated under reduced pressure; the residue wascooled in an ice-water bath to produce more crystalline product. Thismaterial was collected by filtration and washed with hexane, and amixture EtOH/hexane (1/4), it was then dried in a vacuum oven at 63° C.to give 38.01 g of (E)-2-cyano-3-phenyl-acrylic acid ethyl ester (80%combined yield).

Step 2 1-Cyano-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid ethylester

A mixture of (E)-2-cyano-3-phenyl-acrylic acid ethyl ester (83.6 g, 415mmol), 2-nitropropane (37 g, 415 mmol) and potassium carbonate (57.4 g,415 mmol) in EtOH (325 mL) was heated at reflux for 4 hours, then heatedto 50° C. for 18 hours. The reaction mixture was then poured into anaqueous solution of NaCl (15%, 2 L) and extracted with DCM. The organiclayer was separated, dried over Na₂SO₄, filtered, and evaporated underreduced pressure. The residue was purified by distillation under vacuumto give 1-cyano-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid ethylester (64.26 g, 64% yield, pale yellow oil) which distilled at 118° C.(oil bath temperature 157° C.).

Step 3 1-Cyano-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid

A solution of potassium carbonate (40 g) in water (125 mL) was added toa solution of 1-cyano-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acidethyl ester (64.26 g, 264 mmol) in MeOH (500 mL). The reaction mixturewas heated at reflux for 1 hour and then stirred overnight at 85° C. Thevolatiles where evaporated under reduced pressure, and the residue wasdiluted with water and washed twice with EtOAc. The phases wereseparated and the aqueous phase was acidified by addition of HCl(concentrated). Ethyl ether was added and the mixture was carefullyextracted. The organic layer was separated, dried over Na₂SO₄, filteredand evaporated under reduced pressure to give 27.2 g (49% yield) of1-cyano-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid as anoff-white solid.

Step 4 2,2-Dimethyl-3-phenyl-cyclopropanecarbonitrile

To a solution of 1-cyano-2,2-dimethyl-3-phenyl-cyclopropanecarboxylicacid (13.6 g, 63 mmol) in DMSO (125 mL) was added LiCl (10.72 g, 252mmol) followed by NaHCO₃ (7.96 g, 94.5 mmol) and water (4.55 g, 252mmol). Gas evolution was observed, and within 30 minutes enough solidswere dissolved to allow the milky mixture to stir. The reaction mixturewas stirred at 170° C. for 18 hours, then cooled and poured into amixture of water and brine (7/1, 800 mL) and extracted with ethyl ether.The combined organic extracts were dried over Na₂SO₄, filtered andevaporated under reduced pressure to give 7.79 g (76% yield) of2,2-dimethyl-3-phenyl-cyclopropanecarbonitrile (3/1, cis/trans mixture).

Preparation 2 Trans-2,2-Dimethyl-3-phenyl-cyclopropylamine

The synthetic procedure described in this Preparation was carried outaccording to the process shown in Scheme E.

Step 1 Trans-2,2-Dimethyl-3-phenyl-cyclopropanecarboxylic acid

A mixture of 2,2-dimethyl-3-phenyl-cyclopropanecarbonitrile (cis/transmixture, 3.2 g, 18.7 mmol) and freshly ground KOH (3.143 g, 56.1 mmol)in ethylene glycol was heated at 165° C. for 28 hours. The reactionmixture was then cooled and poured into a mixture of water and brine(300 mL). The resulting mixture was extracted 3 times with ethyl ether,the combined organic extracts were dried over Na₂SO₄, filtered andevaporated under reduced pressure to give 3.36 g (95% yield) oftrans-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid.

Step 2 Trans-2,2-Dimethyl-3-phenyl-cyclopropylamine

To a solution of trans-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid(1.78 g, 9.4 mmol) in acetone was added water (4 mL) followed, at −5°C., by ethyl chloroformate (0.982 mL, 10.34 mmol). The reaction mixturewas stirred for 20 minutes and then a solution of sodium azide (731 mg,11.28 mmol) in water (8 mL) was added. The resulting mixture was stirredfor 45 minutes and then diluted with a 1:1 mixture of water and toluene.The organic layer was separated, dried over Na₂SO₄, filtered and heatedat 100° C. for 1 hour. The solvent was then removed under reducedpressure and an aqueous solution of HCl (8 M, 30 mL) was added, and theresulting mixture was heated at reflux for 45 minutes. The reactionmixture was cooled and an aqueous solution of HCl (10%) was added; theresulting mixture was washed with ethyl ether, then basified by additionof NaOH. The resulting mixture was extracted with ethyl ether, and thecombined organic extracts were dried over Na₂SO₄, filtered, andevaporated under reduced pressure to give 1.05 g (70% yield) oftrans-2,2-dimethyl-3-phenyl-cyclopropylamine.

Utilizing the procedure above described and the appropriate startingmaterial,trans-2,2-dimethyl-3-(4-trifluoromethyl-phenyl)-cyclopropylamine wasprepared.

Preparation 3 Cis-2,2-Dimethyl-3-phenyl-cyclopropylamine

The synthetic procedure described in this Preparation was carried outaccording to the process shown in Scheme F.

Step 1 2,2-Dimethyl-3-phenyl-cyclopropanecarboxylic acid amide

Potassium carbonate (467 mg) was added to a solution of2,2-dimethyl-3-phenyl-cyclopropanecarbonitrile (3/1 cis/trans mixture, 4g, 23.4 mmol) in DMSO (7 mL). The resulting mixture was cooled to 0° C.and an aqueous solution of hydrogen peroxide (30%, 2.8 mL) was added.The reaction mixture was allowed to warm up to room temperature and wasstirred overnight. A second aliquot of aqueous solution of hydrogenperoxide (30%, 2.8 mL) was added and the resulting mixture was stirredfor 24 hours. A third aliquot of aqueous solution of hydrogen peroxide(30%, 3.0 mL) was added and the resulting mixture was stirred for 3days. The reaction mixture was poured into brine and extracted withethyl ether. The organic layer was separated, dried over Na₂SO₄,filtered, and evaporated under reduced pressure. The crude residue waspurified by flash chromatography (0% to 65% of EtOAc in hexane) to give2.66 of 2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid amide (2/1trans/cis mixture), together with 1.125 g of starting material.

Step 2 Cis-2,2-Dimethyl-3-phenyl-cyclopropylamine

Bromine (2.2 mL, 42.4 mmol) was added to an aqueous solution of NaOH(10%) at 0° C. The mixture was stirred vigorously, then added to a flaskcontaining cis-2,2-dimethyl-3-phenyl-cyclopropanecarboxylic acid amide(2.01 g, 10.6 mmol) at 0° C. The reaction mixture was heated to 85° C.for 3 hours, then cooled and poured into a mixture of water and brine.The resulting mixture was extracted with ethyl ether, and the combinedorganic extracts were washed twice with an aqueous solution of HCl(10%). The aqueous layer was basified and extracted with ethyl ether.The combined organic extracts were dried over Na₂SO₄, filtered, andevaporated under reduced pressure to give 600 mg of2,2-dimethyl-3-phenyl-cyclopropylamine cis/trans 5/1.

Preparation 4 Trans-2,2-Dimethyl-3-p-tolyl-cyclopropylamine

The synthetic procedure described in this Preparation was carried outaccording to the process shown in Scheme G.

Step 1 2,2-Dimethyl-3-p-tolyl-cyclobutanone

Trifluoroacetic anhydride (25 g, 0.09 mol) was added portionwise over aperiod of 10 minutes at −10° C., to a solution ofN,N-dimethyl-isobutyramide (9.16 g) in DCM (100 mL). The resultingmixture was stirred at −10° C. for 10 minutes and then a viscoussolution of 4-methylstyrene (8.2 g) and collidine (11.9 mL) in DCM (15mL) was added portionwise at −10° C. The resulting mixture was heated atreflux for 22 hours then cooled and concentrated under reduced pressure.The oil residue was washed with ethyl ether and the organic phase wasdecanted away. DCM (75 mL) and water (75 mL) were added to the oil andthe mixture was heated at 100° C. for 6 hours. The mixture was cooled toroom temperature, separated, and the aqueous layer was extracted withDCM. The combined organic extracts were dried over Na₂SO₄, filtered, andevaporated under reduced pressure to give 35 g of crude oil, which waspurified by flash chromatography (5% to 50% of EtOAc in hexane) to give6.45 g (50% yield) of 2,2-dimethyl-3-p-tolyl-cyclobutanone as a yellowoil.

Step 2 Trans-2,2-Dimethyl-3-p-tolyl-cyclopropanecarboxylic acid

A solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 38 mL) wasadded dropwise over a period of 20 minutes at −78° C. to a solution of2,2-dimethyl-3-p-tolyl-cyclobutanone (6.4 g, 34 mmol) in THF (340 mL).The reaction mixture was stirred at −78° C. for 30 minutes and theresulting yellow solution was stirred at 0° C. for 15 minutes; it wasthen cooled again at −78° C. and a solution of N-bromosuccinimide (6.6g) in THF (85 mL) was added dropwise. The resulting suspension wasstirred at 0° C. for 30 minutes, and a solution of NaOH (8.43 g) inwater (85 mL) was then added. The reaction mixture was allowed to warmup to room temperature and was stirred for 1 hour. Volatiles were thenevaporated under reduced pressure. The aqueous residue was extractedwith ethyl ether and the combined organic extracts were dried overNa₂SO₄, filtered, and evaporated under reduced pressure to give 4.2 g ofstaring material. The aqueous layer was diluted with water and acidifieduntil pH 1. by addition of concentrated HCl (25 mL). The resultingmixture was stored in at 4° C. for 2 days, during which time a yellowsolid precipitated. This material was collected by filtration, washedwith cold water and dried to give 3 g (40% yield) oftrans-2,2-dimethyl-3-p-tolyl-cyclopropanecarboxylic acid a yellow solid.

Step 3 Trans-2,2-Dimethyl-3-p-tolyl-cyclopropylamine

Ethyl chloroformate (1.2 mL) was added to a solution oftrans-2,2-dimethyl-3-p-tolyl-cyclopropanecarboxylic acid (2.3 g, 11mmol) and triethylamine (1.7 mL) in a mixture of acetone (15 mL) andwater (2.9 mL). The reaction mixture was stirred for 20 minutes, then asolution of sodium azide (0.81 g) in water (5.8 mL) was added and theresulting mixture was stirred for 45 minutes. The reaction mixture waspartitioned between water and toluene (1/1 mixture, 50 mL), and theorganic layer was separated, dried over Na₂SO₄ and filtered. The organiclayer was heated at 100° C., then cooled and evaporated under highvacuum to give a tan oil. To this oil was added an aqueous solution ofHCl (10 M, 30 mL), and the resulting mixture was heated at 100° C. Thereaction mixture was allowed to cool to room temperature and wasextracted with ethyl ether. The combined organic layers were dried overNa₂SO₄, filtered, and evaporated under reduced pressure to give 1.6 g ofacid starting material. The aqueous layer was basified by addition of anaqueous solution of NaOH,then extracted with DCM. The organic layer wasseparated, dried over Na₂SO₄, filtered, and evaporated under reducedpressure to give 510 mg of trans-2,2-dimethyl-3-p-tolyl-cyclopropylamineas a brown oil.

Example 15-Chloro-N-(trans-2,2-dimethyl-3-phenyl-cyclopropyl)-2-methoxy-benzamide

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme H.

To a solution of trans-2,2-dimethyl-3-phenyl-cyclopropylamine (1.04 g,6.5 mmol) in DCM was added triethylamine (1.435 g, 14.3 mmol), followedby 5-chloro-2-methoxybenzoic acid (1.446 g, 7.44 mmol) andO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(2.696 g, 8.45 mmol). The resulting mixture was stirred at roomtemperature overnight, then poured into water and extracted with DCM.The combined organic extracts were dried over Na₂SO₄, filtered, andevaporated under reduced pressure. The crude residue was purified byflash chromatography (0% to 15% of EtOAc in hexane) to give 1.71 g (86%yield) oftrans-5-chloro-N-(2,2-dimethyl-3-phenyl-cyclopropyl)-2-methoxy-benzamide,MS=330 [M+H]⁺.

In a similar manner, using the appropriate starting material, thefollowing compounds were prepared:

-   -   Cis-5-Chloro-N-(2,2-dimethyl-3-phenyl-cyclopropyl)-2-methoxy-benzamide,        MS=330 [M+H]⁺;    -   Trans-5-Chloro-N-[2,2-dimethyl-3-(4-trifluoromethyl-phenyl)-cyclopropyl]-2-methoxy-benzamide,        MS=398 [M+H]⁺; and    -   Trans-5-Chloro-N-[2,2-dimethyl-3-(4-trifluoromethyl-phenyl)-cyclopropyl]-2,4-dimethoxy-benzamide,        MS=428 [M+H]⁺.

Additional compounds prepared using the above procedure are shown inTable 1.

Example 25-Chloro-N-[Trans-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme I.

Chlorosulfonic acid (0.4 mL) was added dropwise to a solution ofcis-5-chloro-N-(2,2-dimethyl-3-phenyl-cyclopropyl)-2-methoxy-benzamide(119 mg, 0.362 mmol) in chloroform. The reaction mixture was stirred for30 minutes, then poured into a water/ice/brine mixture and extractedwith ethyl ether. The combined organic extracts were dried over Na₂SO₄,filtered, and evaporated under reduced pressure. The residue wasdissolved in 1,4-dioxane and NH₄OH (concentrated) was added. Theresulting mixture was stirred for 45 minutes, then poured into a mixtureof water and brine and extracted with EtOAc. The combined organicextracts were dried over Na₂SO₄, filtered, and evaporated under reducedpressure. The crude residue was recrystallized from DCM to give 10 mg ofcis-5-chloro-N-[2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide.The mother liquors were evaporated under reduced pressure to give amixture of cis and trans products. MS=409 [M+H]⁺.

In a similar manner, using the appropriate starting materials, thefollowing compounds were prepared:

-   -   Cis-5-Chloro-N-[3-(4-dimethylsulfamoyl-phenyl)-2,2-dimethyl-cyclopropyl]-2-methoxy-benzamide,        MS=437 [M+H]⁺; and    -   Trans-5-Chloro-N-[2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide,        MS=409 [M+H]⁺.

Additional compounds prepared using the above procedure are shown inTable 1.

Example 35-Chloro-N-(trans-2,2-dimethyl-3-p-tolyl-cyclopropyl)-2-methoxy-benzamide

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme J.

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide methiodide (130 mg) wasadded at 0° C. to a mixture ofTrans-2,2-dimethyl-3-p-tolyl-cyclopropylamine (70 mg, 0.4 mmol),5-chloro-2-methoxybenzoic acid (75 mg), and 1-hydroxy-7-azabenzotriazole(107 mg) in DCM (2 mL). The reaction mixture was stirred at 0° C. for 30minutes, then allowed to warm to room temperature. The mixture waspartitioned between an aqueous solution of HCl (1 M) and DCM. Thecombined organic extracts were washed with a saturated aqueous solutionof NaHCO₃, dried over Na₂SO₄, filtered, and evaporated under reducedpressure to give 160 mg of a tan foam. This crude residue was purifiedby flash chromatography (0% to 100% Et₂O in hexane) to give 70 mg of5-chloro-N-(trans-2,2-dimethyl-3-p-tolyl-cyclopropyl)-2-methoxy-benzamide,MS=344 [M+H]⁺.

In a similar manner, utilizing the appropriate starting material,5-chloro-N-(trans-2,2-dimethyl-3-p-tolyl-cyclopropyl)-2,4-dimethoxy-benzamidewas prepared; MS=374 [M+H]⁺; MP=148.3-150.9° C.

Additional compounds prepared using the above procedure are shown inTable 1.

Example 4 N-(Trans-2,2-Dimethyl-3-p-tolyl-cyclopropyl)-benzamide

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme K.

Benzoyl chloride (37 μL) was added at 0° C. to a solution oftrans-2,2-dimethyl-3-p-tolyl-cyclopropylamine (50 mg, 0.28 mmol) inpyridine (1 mL). The reaction mixture was slowly allowed to warm up toroom temperature, then was partitioned between an aqueous solution ofHCl (1 M) and DCM. The combined organic extracts were washed with asaturated aqueous solution of NaHCO₃, dried over Na₂SO₄, filtered, andevaporated under reduced pressure to give 50 mg of a tan oil which waspurified by preparative HPLC. A Zorbax 3.5 um, 4.6×50 mm SB-phenylcolumn was used with solvent A (water with 0.1% (V/V) formic acid) andsolventB (acetonitrile), A/B 75/25 from 0 to 1 minute, A/B 5/95 at 6minutes, A/B 75/25 at 6.5 minutes, A/B 75/25 at 7.0 minutes, flow rate1.0 mL/minute. MS=280 [M+H]⁺.

In a similar manner, utilizing the appropriate starting material,N-(trans-2,2-dimethyl-3-p-tolyl-cyclopropyl)-4-methyl-benzamide wasprepared, MS=294 [M+H]⁺.

Additional compounds prepared using the above procedure are shown inTable 1.

Example 55-Chloro-N-[Trans-3-(4-methanesulfonyl-phenyl)-2,2-dimethyl-cyclopropyl]-2-methoxy-benzamide

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme L.

Chlorosulfonic acid (0.17 mL) was added at 0° C. to a solution of5-chloro-N-(Trans-2,2-dimethyl-3-phenyl-cyclopropyl)-2-methoxy-benzamide(165 mg, 0.5 mmol) in chloroform (8 mL), and the resulting mixture wasstirred at room temperature for 1.5 hour. The reaction was then quenchedby addition of ice and the resulting mixture was extracted with diethylether. The combined organic extracts were dried over anhydrous sodiumsulfate, filtered and evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL) and cooled to 0° C. Hydrazine (0.05mL) was added and the resulting mixture was stirred for 18 hours. Thereaction mixture was evaporated under reduced pressure and the residuewas dissolved in ethanol (15 mL). Sodium acetate (205 mg) and methyliodide (355 mg) were added and the resulting mixture was heated toreflux for 18 hours. The reaction mixture was then evaporated underreduced pressure and the residue was partitioned between brine anddiethyl ether. The combined organic layers were dried over anhydroussodium sulfate, filtered and evaporated under reduced pressure. Theresidue was absorbed onto silica gel and purified by flashchromatography (EtOAc/hexane, 0-25%) to give 37 mg of5-chloro-N-[trans-3-(4-methanesulfonyl-phenyl)-2,2-dimethyl-cyclopropyl]-2-methoxy-benzamidecolorless viscous oil.

Example 6 Chiral separation and absolute configuration determination of5-Chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamideand 5-Chloro-N-[(1R,3S)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamide

Trans-5-Chloro-N-[2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamidewas purified by preparative chiral HPLC through multiple injections on aChiralpak AD preparative column (20 mm ID by 250 mm length, 10 micronpacking) using 100% EtOH at 6 ml/min over 30 minutes to give the twoenantiomers:

-   -   Peak #1 retention time 8.9 minutes (−)-enantiomer 883 mg; and    -   Peak #2 retention time 16.9 minutes (+)-enantiomer 875 mg.

These two samples were recrystallized separately. The (−)-enantiomer wasrecrystallized from EtOH (7 mL), and the solid was dried overnight overP₂O₅ at 55° C. This material was then re-dissolved in EtOAc andevaporated under reduced pressure three times. The resulting materialwas then dissolved in DCM and evaporated under reduced pressure fourtimes. The material thus obtained was dried overnight in a drying pistolover refluxing acetone under reduced pressure to give 634.5 mg of afoam, MP=96.3-102.1° C., α_(D)=−109.7° (c=0.518, MeOH).

The (+)-Enantiomer (875 mg) was dissolved in DCM and evaporated underreduced pressure at 60° C. three times. The resulting solid wasdissolved in DCM and hexane was added. The resulting solution wasevaporated under reduced pressure at 65° C., and this operation wasrepeated three times to give a foam that was dried under high vacuumovernight. A portion of this material (182 mg) was recrystallized from2-propanol to give crystals containing one mole of 2-propanol per moleof solvate. The crystal structure of this material was solved by X-raydiffraction and it allowed the determination of the absolute 1R, 3Sconfiguration shown above, α_(D)=+86.2° (c=, MeOH).

Example 75-Chloro-2-methoxy-N-[trans-3-(3-methoxy-phenyl)-2,2-dimethyl-cyclopropyl]-benzamide

The synthetic procedure described in this Example was carried outaccording to the process shown in Scheme M.

Step 1 Trans-3-(3-Methoxy-phenyl)-2,2-dimethyl-cyclopropanecarboxylicacid ethyl ester

Cyclopropanation of 3-methoxy-cinnamic acid methyl ester was carried outfollowing the procedure of Ahmand et al., J Med. Chem 2001, 44,3302-3310. Isopropyl-triphenylphosphonium iodide was prepared asdescribed by Grieco et al., Tet. Lett. 1972, 36, 3781-3783. Briefly, asolution of 3-methoxy-cinnamic acid ethyl ester (14.6 g, 70.9 mmol) in300 mL THF was cooled in a dry ice/acetone bath to approximately −78°C., and added dropwise to a −78° C. stirring solution ofisopropyl-triphenylphosphonium iodide (51 g. 118 mmol) andn-butyl-lithium (54 mL, 135 mmol) in THF. The reaction mixture wasallowed to warm to 0° C. with stirring for two hours, then was stirredat room temperature for 15 hours. The reaction mixture was poured ontoice and the resulting aqueous mixture was adjusted to neutral pH byaddition of 1M aqueous H₂SO₄. The aqueous solution was extracted threetimes with a 1/1 mixture of hexanes/EtOAc and once with EtOAc. Thecombined organic layers were filtered through silica, and the filtratewas dried over MgSO₄, filtered, and concentrated under reduced pressureto give 15.22 g of crudetrans-3-(3-methoxy-phenyl)-2,2-dimethyl-cyclopropanecarboxylic acidethyl ester.

Step 2 Trans-3-(3-Methoxy-phenyl)-2,2-dimethyl-cyclopropanecarboxylicacid

Trans-3-(3-Methoxy-phenyl)-2,2-dimethyl-cyclopropanecarboxylic acidethyl ester (15.22 g, 61 mmol) was added to a mixture of EtOH (200 mL)and 2M aqueous NaOH (100 mL). Solid NaOH (5.0 g, 125 mmol) was added,and the reaction mixture was stirred under N₂ atmosphere for 15 hours atroom temperature. The reaction mixture was diluted with water andextracted twice with a mixture of 1/1 hexanes/diethyl ether and oncewith EtOAc. The combined organic layers were dried (MgSO₄), filtered,and concentrated under reduced pressure to give 11.5 g oftrans-3-(3-methoxy-phenyl)-2,2-dimethyl-cyclopropanecarboxylic acid,MS=221 [M+H]⁺.

Step 3 Trans-3-(3-Methoxy-phenyl)-2,2-dimethyl-cyclopropylamine

Trans-3-(3-Methoxy-phenyl)-2,2-dimethyl-cyclopropylamine was preparedfrom Trans-3-(3-methoxy-phenyl)-2,2-dimethyl-cyclopropanecarboxylic acidfollowing the procedure of step 3 of Preparation 4 above, MS=[M+H]⁺.

Step 45-Chloro-2-methoxy-N-[(Trans-3-(3-methoxy-phenyl)-2,2-dimethyl-cyclopropyl]-benzamide

5-Chloro-2-methoxy-N-[trans-3-(3-methoxy-phenyl)-2,2-dimethyl-cyclopropyl]-benzamidewas prepared by reaction of(trans-3-(3-Methoxy-phenyl)-2,2-dimethyl-cyclopropylamine with3-chloro-5-methoxy-benzoic acid following the procedure of Example 3,MS=360 [M+H]⁺.

Example 8 Formulations

Pharmaceutical preparations for delivery by various routes areformulated as shown in the following Tables. “Active ingredient” or“Active compound” as used in the Tables means one or more of theCompounds of Formula I.

Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0% Lactose 79.5% Magnesium stearate 0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0% Magnesium stearate 0.5% Crosscarmellose sodium 2.0%Lactose 76.5% PVP (polyvinylpyrrolidine) 1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Composition for Oral Administration Ingredient Amount Active compound1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 gPropyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution)12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Colorings 0.5mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation Ingredient % wt./wt. Active ingredient 0.25 gSodium Chloride qs to make isotonic Water for injection  100 ml

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation Ingredient % wt./wt. Active ingredient 1.0%Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

Topical Formulation Ingredients grams Active compound 0.2-2 Span 60 2Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propylparaben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 9 Nicotinic alpha 7 Modulation Assay Cell Cultures

Cell Culture Growth Media: F10 medium (Invitrogen), 2.5% Fetal BovineSerum (FBS, Summit Biotechnology); 15% heat inactivated donor HorseSerum (Invitrogen), 250 μg/ml Hygromycin B (Invitrogen); and 100 nMMethyllicaconite (MLA, Sigma) are added to each new culture by 50-folddilution of stock solution prepared in H₂O at 5μM.

GH₄C₁ cells (rat pituitary-derived cell line) stably expressing humannicotinic alpha7 WT receptor (RPA clone #34.7) are cultivated in cellculture growth media (described above) at 37 C in a humidifiedatmosphere containing 4% CO₂. Fresh cell stock cultures are initiatedwith cells at 0.1-0.2×10⁶/ml, 50 ml media per T225 flask and are grownfor 2 or 3 day prior to use in FLIPR assay. Cells harvested two daysafter intiation of stock flask typically yields ˜25×10⁶/T225 flask and 3days after intiation of stock flask typically yields ˜40×10⁶/T225 flask.

One day prior to assay, cells are placed in in fresh cell culture growthmedia supplemented with 100 nM fresh MLA. To accomplish media change,suspension cells of the culture are removed and 45 ml fresh cell culturegrowth media (containing 100 nM fresh MLA) is immediately added to thestock flask as large numbers of cells remain adherent to the surface.The cells in suspension are then collected by centrifugation,resuspended in 5 ml fresh cell culture growth media and returned to theoriginal culture flask.

Buffer Solutions

Buffer solutions used in the assay are HBSS FLIPR buffer (Invitrogen), 2mM CaCl₂ (Sigma), 10 mM HEPES (Invitrogen), 2.5 mM Probenecid (Sigma),and 0.1% BSA (Sigma)

FLIPR Assay

The alpha 7 nAChR assay is a cell-based functional readout designed todetermine the effect of test compounds to either directly activatenicotinic receptor channels and/or to modulate activation by the nativeagonist acetylcholine (ACh, Sigma).

On day one of the assay, attached cells are lifted using1×-concentration Versene (Gibco, Cat-No. 15040), combined with cells insuspension, and collected by centrifugation (5 min, 162×g). The cellpellet is resuspended in FLIPR buffer at 0.5×10⁶/ml and cells dispensedinto sample wells of a 96-well poly-d-lysine coated black/clear plate(Becton Dickinson) at 0.5×10⁵ cells per well. Sample wells are thensupplemented with FLUO-3AM dye (TefLabs, stock solution prepared at 2.5mM in anhydrous DMSO containing 10% Pluronic acid) in FLIPR buffer at 1μM final assay concentration (FAC). Dye loading of cells occurs byincubation of plates for one hour at 37 C in a humidified atmospherecontaining 4% CO₂. To remove extracellular dye, FLIPR plates are washedusing a Biotek EL405 plate washer leaving a residual volume of 0.1 mlFLIPR buffer per sample well.

Assay of test compound effect on activation of the alpha7 nicotinicreceptor channel is done by measurement of cytosolic [Ca²⁺] elevation asreported by increased FLUO-3 fluorescence using a two additionexperimental design and FLIPR™ (Molecular Devices). Following a 30second baseline recording, test compounds are added online (dilutionscheme below) and cell response is recorded for an additional 5 minutes.After a second addition of ACh (30 μM, FAC), plates are read for anadditional 4 minutes.

Test Compound Preparation

Multiple concentrations of test compounds are examined in parallel oneach 96 well assay plate. In order to achieve 100 μM (1.00E-4 M) for thehighest FAC of test compound, 24 μl of 10 mM test compound stocksolution (100% DMSO) is added directly to 576 μl of FLIPR buffer (i.e.highest [test compound]=0.4 mM=4-fold FAC). Starting with the 0.4 mMtest compound sample, test compounds are then diluted serially in FLIPRbuffer (using Biomek 2000) resulting in the following test compoundFACs:vehicle, 1.00E-4 M, 3.16E-5, 1.00E-5 M, 3.16E-6, 1.00E-6 M,3.16E-7, 1.00E-7 M. Maximum FAC for DMSO=1% in the sample wells exposedto the the highest FAC of test compound of 100 μM. Negative controlswere madeby vehicle addition, followed by ACh addition. Positivecontrols were made by 1 μM PNU-120596 addition, followed by AChaddition.

Compound Activity

Values for IC₅₀/EC₅₀, intrinsic agonist activity and positive allostericmodulation for alpha 7 nAChR were determined using ACTIVITYBASE™ dataanalysis software. For dose-response data, either the fitted mid-pointof the curve (inflection) or the point at which the curve crosses athreshold activity value (typically 50% of control) may be used todetermine IC₅₀/EC₅₀.

Using the above assay, the compounds of the invention were determined tobe positive allosteric modulators for alpha 7 nAChR. For example, thecompound5-Chloro-N-[(1S,3R)-2,2-dimethyl-3-(4-sulfamoyl-phenyl)-cyclopropyl]-2-methoxy-benzamideshowed an EC₅₀ of 0.89, and intrinsic activity of 493.6, and positiveallosteric modulation of 469.6.

Example 10 In vivo Assay for Asthma and Lung Function

BALb/cJ mice are immunized with a standard immunization protocol.Briefly, mice (N=8/group) are immunized i.p. with ovalbumin (OVA; 10 μg)in alum on days 0 and 14. Mice are then challenged with aerosolized OVA(5%) on day 21 and 22. Animals receive vehicle (p.o.) or a compound ofthe invention (100 mg/kg p.o.) all starting on day 20.

Lung function is evaluated on day 23 using the Buxco system to measurePenH in response to an aerosol methacholine challenge. Mice are theneuthanized and plasma samples collected at the end of the study.

Example 11 Formalin Pain Assay

Male Sprague Dawley rats (180-220 g) are placed in individual Plexiglascylinders and allowed to acclimate to the testing environment for 30min. Vehicle, drug or positive control (morphine 2 mg/kg) isadministered subcutaneously at 5 ml/kg. 15 min post dosing, formalin (5%in 50 μl) is injected into plantar surface of the right hind paw using a26-gauge needle. Rats are immediately put back to the observationchamber. Mirrors placed around the chamber allow unhindered observationof the formalin-injected paw. The duration of nociphensive behavior ofeach animal is recorded by a blinded observer using an automatedbehavioral timer. Hindpaw licking and shaking/lifting are recordedseparately in 5 min bin, for a total of 60 min. The sum of time spentlicking or shaking in seconds from time 0 to 5 min is considered theearly phase, whereas the late phase is taken as the sum of seconds spentlicking or shaking from 15 to 40 min. A plasma sample is collected.

Example 12 Colon Pain Assay

Adult male Sprague-Dawley rats (350-425 g; Harlan, Indianapolis, Ind.)are housed 1-2 per cage in an animal care facility. Rats are deeplyanesthetized with pentobarbital sodium (45 mg/kg) administeredintraperitoneally. Electrodes are placed and secured into the externaloblique musculature for electromyographic (EMG) recording. Electrodeleads are tunneled subcutaneously and exteriorized at the nape of theneck for future access. After surgery, rats are housed separately andallowed to recuperate for 4-5 days prior to testing.

The descending colon and rectum are distended by pressure-controlledinflation of a 7-8 cm-long flexible latex balloon tied around a flexibletube. The balloon is lubricated, inserted into the colon via the anus,and anchored by taping the balloon catheter to the base of the tail.Colorectal distension (CRD) is achieved by opening a solenoid gate to aconstant pressure air reservoir. Intracolonic pressure is controlled andcontinuously monitored by a pressure control device. Response isquantified as the visceromotor response (VMR), a contraction of theabdominal and hindlimb musculature. EMG activity produced by contractionof the external oblique musculature is quantified using Spike2 software(Cambridge Electronic Design). Each distension trial lasts 60 sec, andEMG activity is quantified for 20 sec before distension (baseline),during 20 sec distension, and 20 sec after distention. The increase intotal number of recorded counts during distension above baseline isdefined as the response. Stable baseline responses to CRD (10, 20, 40and 80 mmHg, 20 seconds, 4 minutes apart) are obtained in conscious,unsedated rats before any treatment.

Compounds are evaluated for effects on responses to colon distensioninitially in a model of acute visceral nociception and a model of colonhypersensitivity produced by intracolonic treatment with zymosan (1 mL,25 mg/mL) instilled into the colon with a gavage needle inserted to adepth of about 6 cm. Experimental groups will consist of 8 rats each.

Acute visceral nociception: For testing effects of drug on acutevisceral nociception, 1 of 3 doses of drug, vehicle or positive control(morphine, 2.5 mg/kg) are administered after baseline responses areestablished; responses to distension are followed over the next 60-90minutes.

Visceral hypersensitivity: For testing effects of drug or vehicle afterintracolonic treatment with zymosan, intracolonic treatment is givenafter baseline responses are established. Prior to drug testing at 4hours, responses to distension are assessed to establish the presence ofhypersensitivity. In zymosan-treated rats, administration of 1 of 3doses of drug, vehicle or positive control (morphine, 2.5 mg/kg) aregiven 4 hours after zymosan treatment and responses to distensionfollowed over the next 60-90 minutes.

Example 13 Cold allodynia in Rats with a Chronic Constriction Injury ofthe Sciatic Nerve

The effects of compounds of this invention on cold allodynia aredetermined using the chronic constriction injury (CCI) model ofneuropathic pain in rats, where cold allodynia is measured in acold-water bath with a metal-plate floor and water at a depth of 1.5-2.0cm and a temperature of 3-4 ° C. (Gogas, K. R. et al., Analgesia, 1997,3, 1-8).

Specifically, CCI, rats are anesthetized; the trifurcation of thesciatic nerve is located and 4 ligatures (4-0, or 5-0 chromic gut) areplaced circumferentially around the sciatic nerve proximal to thetrifurcation. The rats are then allowed to recover from the surgery. Ondays 4-7 after surgery, the rats are initially assessed for cold-induced allodynia by individually placing the animals in the cold-waterbath and recording the total lifts of the injured paw during a 1-minperiod of time: The injured paw is lifted out of the water. Paw liftsassociated with locomotion or body repositioning are not recorded. Ratsthat displayed 5 lifts per min or more on day 4-7 following surgery areconsidered to exhibit cold allodynia and are used in subsequent studies.In the acute studies, vehicle, reference compound or compounds of thisinvention are administered subcutaneously (s.c.) 30 min before testing.The effects of repeated administration of the compounds of thisinvention on cold allodynia are determined 14, 20 or 38 h following thelast oral dose of the following regimen: oral (p.o.) administration ofvehicle, reference or a compound of this invention at ˜12 h intervals(BID) for 7 days.

Example 14 Cognition Enhancement

The cognition-enhancing properties of compounds of the invention may bein a model of animal cognition: the novel object recognition task model.4-Month-old male Wistar rats (Charles River, The Netherlands) were used.Compounds were prepared daily and dissolved in physiological saline andtested at three doses. Administration was always given i.p. (injectionvolume 1 ml/kg) 60 minutes before T1. Scopolamine hydrobromide wasinjected 30 minutes after compound injection. Two equal testing groupswere made of 24 rats and were tested by two experimenters. The testingorder of doses was determined randomly. The experiments were performedusing a double blind protocol. All rats were treated once with each dosecondition. The object recognition test was performed as described byEnnaceur, A., Delacour, J., 1988, A new one-trial test forneurobiological studies of memory in rats. 1: Behavioral data. Behav.Brain Res. 31, 47-59.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1 A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ar¹ and Ar² eachindependently is: optionally substituted aryl; or optionally substitutedheteroaryl; and R¹ and R² each independently is: hydrogen; fluoro;C₁₋₆alkyl; or halo-C₁₋₆alkyl.
 2. The compound of claim 1, wherein R¹ andR² are C₁₋₆alkyl.
 3. The compound of claim 1, wherein Ar¹ and Ar² areoptionally substituted phenyl.
 4. The compound of claim 1, wherein Ar¹is phenyl optionally substituted with one, two or three groups eachselected independently from halo, halo-C₁₋₆alkyl, C₁₋₆alkyl andC₁₋₆alkoxy.
 5. The compound of claim 1, wherein Ar¹ is5-chloro-2-methoxy-phenyl, 5-chloro-2,4-dimethoxy-phenyl, phenyl,4-methyl-phenyl, 2-methoxy-5-methyl-phenyl, 2-methyl-5-methoxy-phenyl,4-methoxy-2-methyl-phenyl, 2,5-dimethoxy-phenyl, 4-methoxy-phenyl,4-chloro-phenyl, 3,4-dichloro-phenyl, 3-chloro-phenyl, 2-methoxy-phenyl,4-tert-butyl-phenyl, 2,4-dimethoxy-phenyl, 3-trifluoromethyl-phenyl,4-methanesulfonyl-phenyl, 4-aminosulfonyl-phenyl,4-trifluoromethyl-phenyl, 5-fluoro-2-methoxy-phenyl,2-methoxy-5-trifluoromethyl-phenyl, 2-methoxy-5-tert-butyl-phenyl,4-chloro-2-methoxy-phenyl, 2,4,5-trimethoxy-phenyl,2,6-dimethoxy-phenyl, or 2,3-dimethoxy-phenyl.
 6. The compound of claim1, wherein Ar² is phenyl optionally substituted once at the 4-positionwith halo, C₁₋₆alkyl, cyano, halo-C₁₋₆alkyl, C₁₋₆alkoxy or—(CR^(a)R^(b))_(m)—X—R³ wherein: m is 0; X is —SO₂— or —C(O)—; R³ isC₁₋₆alkyl or —NR⁴R⁵, and R⁴ and R⁵ each independently is: hydrogen; orC₁₋₆alkyl.
 7. The compound of claim 1, wherein Ar² is phenyl substitutedat the 4-position with cyano, —SO₂NH₂ or —SO₂—CH₃.
 8. The compound ofclaim 1, wherein Ar² is phenyl, 4-aminosulfonyl-phenyl,4-methylaminosulfonyl-phenyl, 4-dimethylaminosulfonyl-phenyl,4-trifluoromethyl-phenyl, 4-methyl-phenyl, 4-chloro-phenyl,4-methanesulfonyl-phenyl, 4-methoxy-phenyl, 4-cyano-phenyl or4-bromo-phenyl.
 9. The compound of claim 1, wherein R¹ and R² aremethyl.
 10. The compound of claim 1, wherein said compound of formulaII:

wherein: p and q each independently is from 0 to 3; R¹ and R² areC₁₋₆alkyl; and R⁶ and R⁷ each independently is: C₁₋₆alkyl; halo;C₁₋₆alkoxy; halo-C₁₋₆alkoxy; halo-C₁₋₆alkyl; hetero-C₁₋₆alkyl; cyano;C₁₋₆alkyl-amino; di-C₁₋₆alkyl-amino; nitro; and —(CR^(a)R^(b))_(m)—X—R³wherein: m is 0; X is —SO₂—; R³ is C₁₋₆alkyl or —NR⁴R⁵, and R⁴ and R⁵each independently is:  hydrogen; or  C₁₋₆alkyl.
 11. The compound ofclaim 10, wherein R¹ and R² are methyl.
 12. The compound of claim 11,wherein p is from 1 to 3 and each R⁶ is independently: C₁₋₆alkyl; halo;C₁₋₆alkoxy; halo-C₁₋₆alkoxy; or halo-C₁₋₆alkyl.
 13. The compound ofclaim 12, wherein q is 1 and R⁷ is C₁₋₆alkyl, halo-C₁₋₆alkyl or—(CR^(a)R^(b))_(m)—X—R³ wherein: m is 0; X is —SO₂—; R³ is C₁₋₆alkyl or—NR⁴R⁵, and R⁴ and R⁵ each independently is: hydrogen; or C₁₋₆alkyl. 14.The compound of claim 13 wherein p is from 1 to 3 and R⁶ is halo ormethoxy.
 15. The compound of claim 14 wherein q is 1 and R⁷ is—SO₂NR⁴R⁵,
 16. The compound of claim 1, wherein said compound of formulaIII:

wherein: p is from 0 to 3; each R⁶ is independently selected from:C₁₋₆alkyl; halo; C₁₋₆alkoxy; halo-C₁₋₆alkoxy; or halo-C₁₋₆alkyl; and R⁷is —(CR^(a)R^(b))_(m)—X—R³ wherein: m is 0; X is —SO₂—; R³ is C₁₋₆alkylor —NR⁴R⁵, and R⁴ and R⁵ each independently is: hydrogen; or C₁₋₆alkyl.17. The compound of claim 16, wherein p is from 1 to 3 and each R³isindependently halo or methoxy.
 18. The compound of claim 17, wherein R⁷is —SO₂NR⁴R⁵.
 19. The compound of claim 18, wherein R⁴ and R⁵ eachindependently is hydrogen or methyl.
 20. The compound of claim 1,wherein said compound of formula IIIa or IIIb:

wherein p, R⁶ and R⁷ are as recited in claim
 1. 21. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 22. A method for enhancing cognition in subject,said method comprising administering to said subject an effective amountof a compound of claim
 1. 23. A method for preparing a compound offormula r

wherein: Ar¹ and Ar² each independently is: optionally substituted aryl;or optionally substituted heteroaryl; and R¹ and R² each independentlyis: hydrogen; fluoro; C₁₋₆alkyl; or halo-C₁₋₆alkyl; said methodcomprising: reacting a cinnamate compound of formula s

with a Wittig reagent of formula t

to form a cyclopropylester compound of formula u

hydrolyzing said cyclopropyl ester compound of formula u to afford acyclopropyl acid compound of formula p

treating said cyclopropyl acid compound of formula p with chloroformateester, followed by sodium azide and acidification, to afford acyclopropyl amine compound of formula q

reacting said cyclopropyl amine compound of formula q with an acylreagent of formula i

wherein X is hydroxy, halo or alkoxy, to form said compound of formular.